S. R. Sershen

Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance

Metal nanoshells are a class of nanoparticles with tunable optical resonances. In this article, an application of this technology to thermal ablative therapy for cancer is described. By tuning the nanoshells to strongly absorb light in the near infrared, where optical transmission through tissue is optimal, a distribution of nanoshells at depth in tissue can be used to deliver a therapeutic dose of heat by using moderately low exposures of extracorporeally applied near-infrared (NIR) light. Human breast carcinoma cells incubated with nanoshells in vitro were found to have undergone photothermally induced morbidity on exposure to NIR light (820 nm, 35 W/cm2), as determined by using a fluorescent viability stain. Cells without nanoshells displayed no loss in viability after the same periods and conditions of NIR illumination. Likewise, in vivo studies under magnetic resonance guidance revealed that exposure to low doses of NIR light (820 nm, 4 W/cm2) in solid tumors treated with metal nanoshells reached average maximum temperatures capable of inducing irreversible tissue damage (ΔT = 37.4 ± 6.6°C) within 4-6 min. Controls treated without nanoshells demonstrated significantly lower average temperatures on exposure to NIR light (ΔT < 10°C). These findings demonstrated good correlation with histological findings. Tissues heated above the thermal damage threshold displayed coagulation, cell shrinkage, and loss of nuclear staining, which are indicators of irreversible thermal damage. Control tissues appeared undamaged.

Temperature-sensitive polymer/nanoshell composites for photothermally modulated drug delivery

Composites of thermally sensitive hydrogels and optically active nanoparticles have been developed for the purpose of photothermally modulated drug delivery. Copolymers of N-isopropylacrylamide (NIPAAm) and acrylamide (AAm) exhibit a lower critical solution temperature (LCST) that is slightly above body temperature. When the temperature of the copolymer exceeds the LCST, the hydrogel collapses, causing a burst release of any soluble material held within the hydrogel matrix. Gold-gold sulfide nanoshells, a new class of nanoparticles designed to strongly absorb near-infrared light, have been incorporated into poly(NIPAAm-co-AAm) hydrogels for the purpose of initiating a temperature change with light; light at wavelengths between 800 and 1200 nm is transmitted through tissue with relatively little attenuation, absorbed by the nanoparticles, and converted to heat. Significantly enhanced drug release from composite hydrogels has been achieved in response to irradiation by light at 1064 nm. We have investigated the release of methylene blue and proteins of varying molecular weight. Additionally, the nanoshell-composite hydrogels can release multiple bursts of protein in response to repeated near-IR irradiation.

Implantable, polymeric systems for modulated drug delivery.

The ability to deliver therapeutic agents to a patient in a pulsatile or staggered release profile has been a major goal in drug delivery research over the last two decades. This review will cover methods that have been developed to control drug delivery profiles with implantable polymeric systems. Externally and internally controlled systems will be discussed, spanning a range of technologies that include pre-programmed systems, as well as systems that are sensitive to modulated enzymatic or hydrolytic degradation, pH, magnetic fields, ultrasound, electric fields, temperature, light and mechanical stimulation. Implantable systems have the potential to improve the quality of life for patients undergoing therapy with a variable dosing regime by eliminating the need for multiple intravenous injections. Ideally, these systems would also result in increased patient compliance with a given therapy due to the relative ease of self-dosing.

Independent optically addressable nanoparticle-polymer optomechanical composites

We report the fabrication and characterization of optomechanically active composite materials consisting of a thermally responsive poly(NIPAAm-co-AAm) hydrogel matrix incorporating a dilute concentration of Au or silica-Au core-shell nanoparticles. Under optical illumination at the resonance absorption wavelength of the nanoparticle dopant, a dramatic volume collapse of the composite occurs due to local photothermal heating of the NIPAAm matrix. Nanoparticle dopants were chosen so that each composite was specifically optically addressable, exhibiting optomechanical behavior at independent wavelengths. Such materials can be useful as independently addressable remotely triggerable switches and gates in a wide variety of micromechanical applications.

Targeted photothermal tumor therapy using metal nanoshells

Complications associated with invasive malignant tumor excision have led to alternative treatment methods including chemotherapy, photodynamic therapy, and thermal coagulation. Metal nanoshells, which are a new class of optically active nanoparticles, may provide a novel means of targeted photothermal therapy in tumor tissue, minimizing damage to surrounding healthy tissue. Metal nanoshells possess a strong tunable absorption, which can be placed in the near IR where maximal penetration of light through tissue is achieved. When conjugated with a tumor-specific protein, these nanoshells could be systemically injected, but preferentially bound to the tumor site. Near IR light administered at the site would heat the localized nanoshells, killing the tumor. We have successfully conjugated antibodies against oncoproteins to nanoshells and demonstrated specific binding to tumor cells. Furthermore, we have demonstrated photothermally-induced death of nanoshell-bound carcinoma cells in vitro, as well as in vivo. These studies utilized an 821 nm diode laser, and nanoshells fabricated with their plasmon resonance at 821 nm. Cell death was limited to the laser spot, and under control conditions (no nanoshells or no light), no cell death or tissue damage was observed.

Nanoshell-mediated near infrared photothermal tumor therapy

A novel photothermal therapy of neoplastic tissue is described. The use of near infrared (NIR) absorbing nanoshells permits targeted photothermal ablation of tumor tissue via NIR heating of nanoshell-laden tumors using an extracorporeal near infrared source. Human breast carcinoma cells incubated with nanoshells in vitro were found to undergo photothermally induced morbitity upon exposure to NIR light (820 nm, 44 W/cm/sup 2/) as determined using a fluorescent viability stain. Cells without nanoshells displayed no loss in viability after the same periods and conditions of near infrared illumination. Likewise, in vivo studies under MR guidance revealed that exposure to low doses of near infrared light (820 nm, 4 W/cm/sup 2/) in solid tumors treated with metal nanoshells reached average temperatures capable of inducing irreversible tissue damage (/spl Delta/T=37.4/spl plusmn/6.6/spl deg/C) within 4-6 minutes. Controls treated without nanoshells demonstrated significantly less average temperatures upon exposure to near infrared light (/spl Delta/T<10/spl deg/C). These findings demonstrated good correlation with histological findings. Tissues heated above the thermal damage threshold displayed coagulation, cell shrinkage, and loss of nuclear staining-indicators of irreversible thermal damage. Control tissues did not display these indicators and appeared undamaged.

Pulsatile release of insulin via photothermally modulated drug delivery

Composites of thermally-sensitive hydrogels and optically-active nanoparticles have been developed for transdermal photothermally modulated drug delivery. Copolymers of N-isopropylacrylamide (NIPAAm) and acrylamide (AAm) exhibit a lower critical solution temperature (LCST) that is slightly above body temperature. Gold-gold sulfide nanoshells have been incorporated into poly(NIPAAm-co-AAm) hydrogels to initiate a temperature change with light. The nanoshells heat upon irradiation at their peak absorption wavelength, causing the collapse of the polymer and the subsequent release of any drug contained within the polymer matrix. For this to occur, the light must pass through the skin and retain enough power to cause significant heating in the nanoshells. Light between 800 and 1200 nm has been shown to have relatively lour levels of attenuation in tissue. Composite polymers of the nanoshells and NIPAAm-co-AAm can deliver controlled pulsatile doses of insulin in response to near-IR irradiation. The activity of the released insulin was determined by measuring glucose uptake by adipocytes that had been exposed to photothermally released insulin. The released insulin did not show a loss in activity as compared to the positive control (insulin in saline), thus demonstrating transdermal photothermally modulated drug deliver in vitro.

Nanoshell-polymer composites for photothermally modulated drug delivery

Summary form only given. Optically active gold nanoshells; have been incorporated into thermally, responsive copolymers of N-Isopropylacrylamide (NIPAAm) and acryl-amide (AAm) for the purpose of photothermally modulated drug delivery. The copolymer exhibits a lower critical solution temperature (LCST) that is slightly above body, temperature. When the temperature of the hydrogel exceeds its LCST, a rapid collapse occurs, expelling any material contained within the hydrogel. The gold nanoshells initiate a temperature increase, via targeted absorption of near IR light.

Optically controllable materials: potential valves and actuators in microfluidics and MEMS

Composite materials consisting of optically active nanoparticles embedded within a thermally sensitive polymer selectively collapse when irradiated by light that matches the peak absorbtion wavelength of the nanoparticles. A copolymer of N-isopropylacrylamide and acrylamide exhibits a lower critical solution temperature (LCST) that is dependent on the relative amounts of each monomer in the polymer. Raising the temperature of the copolymer above the LCST initiates a rapid, reversible collapse. Optically active nanoparticles have been incorporated into NIPAAm/AAm hydrogels for the purpose of initiating a temperature increase via targeted absorption of near IR and green light. Gold nanoshells consist of a thin layer of gold surrounding a silica core, and altering the core/shell ratio allows the absorption of the nanoshells to be tuned over the visible and near IR spectrum. Gold colloid absorbs green light strongly at 532 nm. Two sets of composite hydrogels were fabricated, each containing one of the two nanoparticles. The nanoshell-composite hydrogels collapse in response to near-infrared irradiation but do not react to green light. The opposite behavior occurs for the colloid-composite hydrogels. This independent optical addressability should prove useful in a wide range of applications such as microfluidics and MEMS.